This project is a direct complement to project 4. We have established both the tryptophan depletion paradigm and AMPT depletion paradigm. The main focus of the ongoing project using these techniques on the GCRC is on hostility. We will study patients with a prior history of vascular depression who are not currently depressed and not on medications. Since we have a longitudinal study of depression we have a cohort of patients who would satisfy this requirement. The depletion paradigm will test the hypothesis that catecholamine and serotonin depletion can precipitate depression in subjects with vascular changes. If the hypothesis is valid it provides support for the one component of the circuit. The project is innovative in that it directly tests the importance of NE and serotonin in inducing depression in a known high risk population with defined damage to the circuits of relevance. The study has the potential to elucidate critical interaction, many of which have remained assumptions shaping many of our current theories of depression.